Neuropathic Charcot arthropathy is a complication of diabetes mellitus which in a high percentage of patients leads to foot fracture, joint destruction (subluxation and/or dislocation), severe foot deformity, ulceration, instability, and possibly amputation. Early detection and timely intervention are necessary to minimize the severe consequences of this increasingly prevalent condition. The development of new treatments is currently limited, however, by the lack of biomarkers that are sensitive and specific indicators of neuropathic Charcot arthropathy disease onset and treatment outcomes. Our long term goals are to improve neuropathic Charcot arthropathy treatments and to identify subjects who are at high risk for developing this debilitating complication. There is evidence that those with neuropathic Charcot arthropathy have low foot bone mineral densities (BMDs) and that foot BMDs further decrease during off-loading treatment. The objectives of this pilot data application are to establish volumetric quantitative computed tomography (VQCT)-derived foot BMD as a candidate biomarker for acute neuropathic Charcot arthropathy and to collect preliminary data for sample-size calculations in support of future studies to qualify foot BMD as a biomarker of neuropathic Charcot arthropathy. This pilot grant application has two specific aims: 1) to demonstrate the extent to which VQCT-derived foot BMDs predict treatment outcomes in subjects with diabetes mellitus, peripheral neuropathy, and acute neuropathic Charcot arthropathy and 2) determine the feasibility of using VQCT-derived foot BMDs to assess the risk of developing neuropathic Charcot arthropathy in subjects with diabetes mellitus and peripheral neuropathy. These specific aims will be achieved through a repeated measures cohort study in which clinical and radiological data will be collected: (1) at baseline, three months, six months and yearly for subjects who have neuropathic Charcot arthropathy and are undergoing the standard off-loading treatment protocol (Aim 1), and (2) at baseline and yearly for subjects with diabetes and peripheral neuropathy but who have not developed neuropathic Charcot arthropathy (Aim 2). Analysis of the baseline and follow-up changes will determine the extent to which VQCT-derived foot BMDs are indicators of treatment outcomes (Aim 1). Aim 2 subjects will be compared to Aim 1 subjects to determine the ability of volumetric foot BMD to estimate the risk for developing neuropathic Charcot arthropathy. Developing biomarkers in this area is significant because it can lead to identifying subjects at risk for developing neuropathic Charcot arthropathy and support the development of new treatment regimens that reduce the number of severe complications for this important patient group. [unreadable] [unreadable] [unreadable]